This renewal application focuses on characterizing the capability of young human infants to generate HIV-1 specific CD8+ CTL responses and the potential role of these responses in the pathogenesis of vertical infection. Collectively, these projects address the hypothesis that the role of HIV-1 specific CTL in controlling viremia and protecting against disease progression following vertical infection is dependent not only on the timing of detection, magnitude, and breadth of the responses but also on CTL functional properties. Novel and sensitive assay systems (MHC-peptide tetramers, ELISPOT assays, intracellular cytokine assays) have enhanced the detection and characterization of virus-specific CD8+ T cell responses in the peripheral blood. These novel methods will be used to address the following specific aims: 1) To examine the timing of detection, magnitude, specificity, and in vitro functional properties of HIV-1 specific CD8+ CTL in infants; 2) To evaluate the effects of potent combination antiretroviral therapy on HIV-1 specific CD8+ CTL in infants; and 3) To evaluate the immunogenicity of recombinant pox-based vaccines in HIV-1 infected infants with prolonged viral suppression following early potent combination antiretroviral therapy. Data from these studies will be helpful in better understanding the pathogenesis of vertical HIV-1 infection and for the development of a neonatal vaccine to interrupt vertical HIV-1 transmission.